ImmunoSensation - the immune sensory system

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Biol Blood Marrow Transplant. 2018 Dec 3.

Phase I/II trial of a combination of anti-CD3/CD7 immunotoxins for steroid-refractory acute graft-versus-host disease.

Groth C, van Groningen LFJ, Matos TR, Bremmers ME, Preijers FWMB, Dolstra H, Reicherts C, Schaap NPM, van Hooren EHG, IntHout J, Masereeuw R, Netea MG, Levine JE, Morales G, Ferrara JL, Blijlevens NMA, van Oosterhout YVJM, Stelljes M, van der Velden WJFM

Effective therapies for treating patients with steroid-refractory acute graft-versus-host-disease (SR-aGvHD), particularly strategies that reduce the duration of immunosuppression following remission, are urgently needed. The investigated immunotoxin-combination consists of a mixture of anti-CD3 and anti-CD7 antibodies separately conjugated to recombinant ricin A (CD3/CD7-IT), which induces in-vivo depletion of T- and NK-cells and suppresses T-cell receptor activation. We conducted a phase I/II trial in order to examine the safety and efficacy of CD3/CD7-IT in 20 patients with SR-aGvHD; 17 of these patients (85%) had severe SR-aGvHD, and all 20 patients had visceral organ involvement; 18 gastrointestinal (GI) (90%) and 5 liver (25%) involvement. A validated two biomarker algorithm classified the majority of patients (11/20) as high-risk. On day 28 after the start of CD3/CD7-IT, the overall response rate was 60% (12/20), with 10 patients (50%) achieving a complete response; moreover, the 6-month overall survival rate was 60% (12/20), including 64% (7/11) classified as high risk by biomarkers. The one-week treatment course with CD3/CD7-IT caused profound but transient depletion of T- and NK-cells, followed by rapid recovery of the immune system with a diverse TCR Vβ repertoire, and preservation of EBV- and CMV-specific T-cell clones. Furthermore, our results indicate that CD3/CD7-IT appeared to be safe and well-tolerated, with a relatively low prevalence of manageable and reversible adverse events, primarily worsening of hypoalbuminemia, microangiopathy, and thrombocytopenia. These encouraging results suggest that CD3/CD7-IT may improve patient outcomes in patients with SR-aGVHD. This trial was registered at www.clinicaltrials.gov as #NCT02027805.

PMID: 30399420